The Ratio of Monomeric to Aggregated Forms of Aβ40 and Aβ42 Is an Important Determinant of Amyloid-β Aggregation, Fibrillogenesis, and Toxicity

Asad Jan,Ruth Luthi-Carter,Hilal A. Lashuel,Ozgun Gokce

doi:10.1074/jbc.m803159200

Abstract

Aggregation and fibril formation of amyloid-beta (Abeta) peptides Abeta40 and Abeta42 are central events in the pathogenesis of Alzheimer disease. Previous studies have established the ratio of Abeta40 to Abeta42 as an important factor in determining the fibrillogenesis, toxicity, and pathological distribution of Abeta. To better understand the molecular basis underlying the pathologic consequences associated with alterations in the ratio of Abeta40 to Abeta42, we probed the concentration- and ratio-dependent interactions between well defined states of the two peptides at different stages of aggregation along the amyloid formation pathway. We report that monomeric Abeta40 alters the kinetic stability, solubility, and morphological properties of Abeta42 aggregates and prevents their conversion into mature fibrils. Abeta40, at approximately equimolar ratios (Abeta40/Abeta42 approximately 0.5-1), inhibits (> 50%) fibril formation by monomeric Abeta42, whereas inhibition of protofibrillar Abeta42 fibrillogenesis is achieved at lower, substoichiometric ratios (Abeta40/Abeta42 approximately 0.1). The inhibitory effect of Abeta40 on Abeta42 fibrillogenesis is reversed by the introduction of excess Abeta42 monomer. Additionally, monomeric Abeta42 and Abeta40 are constantly recycled and compete for binding to the ends of protofibrillar and fibrillar Abeta aggregates. Whereas the fibrillogenesis of both monomeric species can be seeded by fibrils composed of either peptide, Abeta42 protofibrils selectively seed the fibrillogenesis of monomeric Abeta42 but not monomeric Abeta40. Finally, we also show that the amyloidogenic propensities of different individual and mixed Abeta species correlates with their relative neuronal toxicities. These findings, which highlight specific points in the amyloid peptide equilibrium that are highly sensitive to the ratio of Abeta40 to Abeta42, carry important implications for the pathogenesis and current therapeutic strategies of Alzheimer disease.

Highlights

(A␤)2 proteins in the form of diffuse and neuritic plaques in regions of the brain that are affected by the disease [1,2,3,4]
Potential interactions between A␤40 and A␤42 have been investigated previously by various research groups. These studies have shown that A␤40 can inhibit the aggregation and fibril formation of A␤42 [38, 41] and protect cultured neurons from A␤-induced neurotoxicity [40]
Unlike previous studies suggesting that A␤40 blocks the aggregation of monomeric A␤42 [41], our results show that A␤40 does not prevent further aggregation of the various A␤42 quaternary structures

Summary

Introduction

(A␤) proteins in the form of diffuse and neuritic plaques in regions of the brain that are affected by the disease [1,2,3,4]. Animal models and in vitro cell culture studies have shown that, in most instances, FAD mutations enhance total A␤ production, promote its aggregation and brain deposition, and/or alter the A␤40/A␤42 ratio in favor of A␤42 production (28 –30). To evaluate the consequences of altering the ratio A␤40/A␤42, several groups have investigated the effect of co-expressing the two A␤ variants (A␤40 and A␤42) or altering the expression level of one or the other variant in cellular and animal models of AD These studies and other studies in human patients demon-. We determined the preferential effect of A␤40 on the kinetic stability, solubility, and fibrillogenesis rate of specific aggregation states of A␤42, including monomers, protofibrils, and fibrils. We explored the dynamics of exchange between monomeric A␤40 and A␤42 at the end of protofibrils and fibrils formed by each peptide and determined the effect of these interactions on the aggregate growth and morphology in vitro. The implications of these findings for intervention strategies for AD are discussed

Results

Discussion

Conclusion